Are You Confident of the Diagnosis?

Livedo reticularis (LR), which is more descriptive of a physical finding than a diagnosis, is a netlike or reticulated red to bluish discoloration of the skin related to the vasculature. More commonly, LR is observed on the lower extremities as a physiologic response to cold temperature that resolves with warming. However, LR is also associated with a number of underlying systemic conditions. As such, LR is commonly classified either as primary or secondary based on the absence or presence of an underlying disease. The term livedo racemosa has been used to connote the presence of livedo reticularis in pathologic states.

What you should be alert for in the history

History is focused on identifying the presence of an underlying disease, which would guide workup and management.

LOCATION

Where is the discoloration?

While most commonly noted on the legs, LR may be observed on the trunk or it may be generalized.

DURATION

Is LR transient or persistent?

Idiopathic LR, one of the three types of LR not associated with systemic features, is persistent, while both physiologic and primary LR fluctuate in course.

ALLEVIATING/EXACERBATING FACTORS

Are there changes in appearance with ambient temperature?

Physiologic LR is induced by cold temperatures while primary and idiopathic LR are not sensitive to temperature change. While cold typically accentuates intensity of discoloration, livedo racemosa remains fixed and present in spite of warming of the skin.

MEDICAL HISTORY

A detailed medical history is important to identify cases associated with systemic disease. Is there a history of autoimmune disease? Are there symptoms to suggest autoimmune disease? LR may be a manifestation of systemic lupus erythematosus (SLE), dermatomyositis, scleroderma, rheumatic fever, or rheumatoid arthritis.

Does the patient have Raynaud's phenomenon? The presence of Raynaud's suggests a predilection towards vasospasm.

Is there a history of chronic renal disease? Calciphylaxis may present with LR.

Is there a predisposition for hypercoagulable states? Personal or family history of thromboembolic disease or early stroke should be elicited. Personal history of malignancy, which is associated with a hypercoagulable state, should be elicited.

Does the patient have any history of recent infection? Mycoplasma, syphilis, hepatitis C, parvovirus, meningococcemia, pneumococcal sepsis, and tuberculosis (TB) have all been associated with LR

Have any new medications been started? Amantadine, minocycline, norepinephrine, interferon, and quinine represent the most frequently reported causes of medication-induced LR; however, gemcitabine, thrombolytics, heparin, and bismuth have also been reported to induce LR.

Has the patient undergone any recent vascular studies? Arteriography/catheterization may lead to cholesterol emboli syndrome and resultant LR.

A detailed review of systems can also be helpful in uncovering any systemic conditions such as autoimmune disease.

Characteristic findings on physical examination

Mottled, netlike pattern of blue-red to violaceous interconnecting patches of rings on the skin (Figure 1).

Figure 1.

Livedo reticularis

Physiologic LR: Discoloration is more faint and network is narrow-based. Most commonly on lower extremities and less frequently on upper extremities or trunk. Transient and resolves with warming.

Secondary LR: Discoloration is more intense and network is wide based or in starburst patterns. May involve buttocks and upper extremities. These features comprise the finding termed livedo racemosa (Figure 2).

Figure 2.

Livedo racemosa

Look for clues on physical examination that may suggest associated systemic disease:

- Presence of purpura, necrosis, and ulceration should raise suspicion for conditions associated with either vessel wall pathology (vasculitis or calciphylaxis) or intraluminal obstruction of the small vessels with either emboli or thromboses.

- Palpable purpura is the most common finding in small-vessel vasculitis.

- Lower extremity nodules and ulcerations are findings that suggest medium-sized vasculitides such as polyarteritis nodosa.

- Purpuric eruption in different stages from papules to hyperpigmented macules, typically on the lower extremities, may suggest cryoglobulinemia.

Be on the lookout for findings suggestive of an associated collagen vascular disorder, which may include one of the following:

Expected results of diagnostic studies

BIOPSY

Skin biopsy for LR may have poor sensitivity in detecting vessel wall or lumen pathology since sampling error is common. Incisional biopsy to fascia should be considered to capture medium-ized vessels. Ideally, the sample crosses blanched as well as bluish areas, as the site of pathology along the vessel wall may correspond to either area depending on the etiology.

Primary/physiologic LR: may have no observable microscopic pathology

Secondary LR: varied, depending on etiology and may include

- Fibrin deposition in vessel walls and leukocytoclasia — Vasculitis

- Intraluminal thrombosis — Hypercoagulable states

- Calcium deposition in vessel walls — Calciphylaxis

- Intravascular eosinophilic plugging — Monoclonal cryoglobulinemia

- Cholesterol clefting — Cholesterol emboli syndrome

SEROLOGY

Serologic workup varies by etiology and should be directed by the clincial assessment

Sjögren's Syndrome: Anti-Ro (SS-A) is positive in 50% of patients with primary Sjögren's. Anti-La (SS-B) is positive in 50% of patients and may be absent if Anti-Ro antibody is also absent. ANA may also be positive. Elevated titer rheumatoid factor. Check a CBC for anemia.

Systemic Sclerosis: Anti-centromere and anti-topoisomerase I DNA (Scl70) antibodies may be positive in scleroderma.

Cryoglobulinemia: A livedoid pattern of erythema is typical in type I monoclonal cryoglobulinemia. Check serum cryoglobulins, SPEP, UA, CBC, serum chemistries, liver function tests. Cryofibrinogens are fibrinlike proteins found in plasma that also can induce a temperature dependent hyperviscosity state that can present as LR. For diagnosis, blood must be collected in an anticoagulated tube and centrifuged at 37 degrees Celsius.

Infections: Infections may be associated with the presence of LR. Consider checking cold agglutinins in suspected cases of mycoplasma infection

Diagnosis confirmation

There are other dermatologic conditions in which the findings may appear similar to LR. Patients with livedoid vasculopathy often have red to purple and often purpuric tightly reticulated erythema, localized to the area of involvement. Small ulcers and stellate white scars are also present. In erythema ab igne, there is fixed, wide-based reticulated, more brown than red or purple erythema of the skin. In reticular erythematous mucinosis, erythematous papules rather than patches comprise the reticular pattern on the midline trunk rather than the extremities. Viral exanthems, notably parvovirus B19, may also cause the appearance of faint pink, finely networked reticulated erythema.

Who is at Risk for Developing this Disease?

Given the widespread and benign nature of physiologic livedo, epidemiologic data are limited; however, it is most commonly seen in young to middle-aged women.

Risk factors associated with the occurrence of secondary LR parallel those associated with the underlying disease.

What is the Cause of the Disease?

Etiology

Pathophysiology

A number of causes of LR exist, however the main pathophysiologic change is the alteration of bloodflow through the cutaneous microcirculation. Any process that decreases blood flow to and through the skin or reduces drainage of blood out of the skin will result in accumulation of deoxygenated blood in the venous plexus and thus appearance of LR.

There are three main causes for LR not associated with systemic disease

Physiologic LR, also known as cutis marmorata, refers to a normal pattern response to cold temperatures. It is most commonly seen in neonates and young children. Cold temperature results in increased viscosity through the superficial venous plexus, which leads to venous dilation and appearance of LR.

Primary LR is intermittent, like physiologic LR, though it is independent of ambient temperature. It is thought that spontaneous arteriolar vasospasm results in decreased arteriolar inflow and a resultant increase in deoxygenated venous blood. Elevation of the involved limb improves LR, which suggests that venous outflow is not impaired.

Idiopathic LR refers to persistent LR with no known underlying cause. There is no resolution with warming of the skin. Patients may report numbness and tingling with cold exposure. This condition is seen in women most commonly.

Systemic Implications and Complications

While secondary LR is associated with systemic disease, the underlying pathophysiology is fundamentally the same as that seen in primary LR where decreased flow through arterioles in the skin results in subpapillary venous dilation. Thus, LR may be the result of any condition that causes vasospasm, intraluminal obstruction, or vessel wall pathology.

CONGENITAL

Cutis marmorata telangiectatica congenita: This uncommon condition presents at birth. it is usually confined to one lower extremity, though it may also be localized to the abdomen or be generalized. Patients also have telangiectasias as well as other vascular anomalies, and there may also be limb or body asymmetry. Cutaneous findings tend to improve spontaneously over first few years of life.

HYPERCOAGULABLE STATES

Antiphospholipid syndrome (APLS): LR is associated with the presence of antiphospholipid antibodies. One study showed that 40% of patients with APLS had LR as the presenting sign. These patients should be evaluated for the presence of lupus anticoagulant, anticardiolipin and beta 2 glycoprotein antibodies.

Coagulopathies related to protein C and S or antithrombin III deficiencies are also associated with LR. Homocysteinemia and homocysteinuria are disorders associated with disruption in methionine metabolism leading to hypercoagulability. Homocysteine levels may be increased in blood and urine.

HYPERVISCOSITY STATES

Polycythemia vera: Sluggish flow through cutaneous microvasculature due to increased viscosity from an increased number of red blood cells in polycythemia vera may result in LR. Additional cutaneous findings include erythromelalgia, ruddiness of the face, and occasionally acral cyanosis.

Paraproteinemia/ multiple myeloma: The increase in circulating immunoglobulins also leads to sluggish flow and results in LR.

VESSEL WALL PATHOLOGY

The most common cause of LR is vasculitis involving medium-sized arterioles at the dermis-subcutis junction (ie, polyarteritis nodosa, Wegener's granulomatosis). Additionally, LR has been described in large-vessel vasculitis (ie, Takayasu's arteritis).

Calciphylaxis: Deposition of calcium within vessel walls leads to LR, which is followed by purpura and necrosis of skin. This condition is seen most commonly in the setting of chronic renal failure, though there are cases of calciphylaxis reported in patients with no renal disease.

AUTOIMMUNE DISEASES

Among autoimmune diseases, LR is most commonly associated with SLE, systemic sclerosis, and Sjögren's disease, though it has also been reported in association with dermatomyositis and Still's disease. Cases of LR in patients with rheumatoid arthritis should raise immediate concern for rheumatoid vasculitis. In connective tissue diseases, the tendency for vasospasm may lead to the development of LR. Thus, it is commonly seen in connective tissue diseases in which Raynaud's phenomenon is also common.

EMBOLIC DISEASE

Cholesterol emboli syndrome is commonly seen after vascular manipulation, such as catheterization, resulting in dislodgement of cholesterol plaques from the vessel wall and subsequent embolization and obstruction of distal cutaneous microvasculature. This syndrome presents with limb pain, fixed LR, renal failure, peripheral eosinophilia, and intact peripheral pulses. Following the development of LR, patients may develop purpura, cyanosis, necrosis, ulceration, and gangrene.

Atrial myxomas may shower myxomatous emboli to cutaneous vasculature and result in LR.

MEDICATIONS

Amantadine has been classically associated with LR. The mechanism is hypothesized to be related to a combination of catecholamine-Induced vasospasm and the effects of amantadine on N-methyl-D aspartic acid receptors in the skin. The livedo will resolve upon withdrawal of amantadine.

Long-term minocycline use has been reported to induce a polyarteritis nodosa-like syndrome with fever, fatigue, arthritis, LR, and positive p-ANCA. Cessation of minocycline resulted in resolution.

Sneddon syndrome is characterized by cerebrovascular infarctions and widespread livedo racemosa seen in young to middle-aged women. LR often precedes the onset of stroke by many years.

Treatment Options

Instruction Treatment options are summarized in the Table I.

Optimal Therapeutic Approach for this Disease

LR without systemic associations does not require treatment. There is limited literature regarding efficacy of various therapies in improving the appearance of LR, and most evidence is anecdotal. Patients with physiologic LR should be counseled to avoid prolonged cold exposures. Compression stockings and limb elevation may result in transient improvement. Medical therapies resulting in vasodilitation may also be considered. Nifedipine, which has been shown in controlled double-blind studies to be effective in Raynaud's phenomenon, may also be effective for vasospastic LR. Pentoxifylline increases erythrocyte deformability and reduces platelet aggregation and activation and may also be beneficial in primary or secondary LR.

The therapeutic approach to LR associated with systemic disease can be approached by classifying the etiology as either inflammatory or non-inflammatory. The complexities around managing each primary disease with which LR is associated is beyond the scope of this clinical decision support, and the dermatologist encountering such conditions should consider seeking the interdisciplinary collaboration of the appropriate specialist.

Treatment of inflammatory causes of livedo reticularis

The mainstay of management of vasculitis resulting in LR is the use of anti-inflammatory agents, including nonsteroidai anti-inflammatory agents, systemic corticosteroids, and systemic immunosuppressants.

Treatment of non-inflammatory causes of livedo reticularis

Hypercoagulable states: Anticoagulant therapy such as with aspirin or coumadin is generally recommended in patients with hypercoagulable states associated with LR. These clinical scernarios represent an important opportunity for dermatologists to engage in a multidisciplinary approach involving possibly rheumatologists and hematologists.

Hyperviscosity states: Polycythemia vera treatment is focused on maintaining a low hematocrit (less than 45% in men and 43% in women.) Thus, phlebotomy alone is effective though patients may also receive supplemental hydroxyurea or anagrelide. Additionally, all PCV patients should be given low-dose aspirin.

Vessel obstruction: If cholesterol embolism is suspected as the underlying cause of livedo, long-term management is directed toward removing and modifying precipitating risk factors. Anticoagulants play a controversial role in CES since they are also implicated in disrupting the fibrin caps that hold cholesterol plaques in place adjacent to the vessel wall.

Medications: Amantadine-induced livedo is a reversible side effect that resolves over time after cessation of the medication. Additionally, the lupus-like syndrome associated with minocycline is slowly reversible upon withdrawal of the drug.

Infections: LR usually improves when the underlying infection is treated or resolves.

Neurologic: Reflex sympathetic dystrophy is a complex condition with little evidence-based treatment. Treatment generally focuses on sympathetic blockade and anti-inflammatory agents, though these treatments are not effective in modifying cutaneous symptoms. The treatment of Sneddon syndrome is controversial. Corticosteroids have proved to be ineffective. Generally, anticoagulation is recommended. Management should be coordinated with rheumatology and neurology.

Patient Management

Patients with isolated asymptomatic LR do not require additional monitoring or special follow-up. The follow-up for patients with systemic conditions associated with LR should be individualized and based on the underlying condition and in collaboration with the other specialists.

Unusual Clinical Scenarios to Consider in Patient Management

LR associated with systemic conditions may present with livedo in an asymmetric, wide-based, jagged edged, broken-ring pattern that is referred to as livedo racemosa. Livedo racemosa may also be accompanied by purpura, nodules, ulcers, and atrophie blanche-type scarring. Livedo racemosa has also historically been referred to as “pathologic livedo reticularis” because of its association with anti-phospholipid syndrome and Sneddon's syndrome.